Busulfan Fludarabine (BU-FLU) Compared to Thiotepa Busulfan Fludarabine (TBF) for Allogeneic Transplants in Acute Myeloid Leukemia (AML) or Refractory Anemia with Excess Blasts (RAEB) in Remission

INTRODUCTION The combination of Busulfan and fludarabine (BU-FLU) is considered a standard conditioning regimen for patients with acute myeloid leukemia undergoing an allogeneic hemopoietic stem cell transplant (HSCT) , especially in patient older than 40 years of age. However, in a recent prospective study, designed for patients in first or second remission (CR1 or CR2) the incidence of leukemia relapse at 3 years was 38%, both for patients receiving BU-FLU as well as for patients randomized to BU-CY (Lancet Oncol 2015;16:1525). The addition of thiotepa to a BU-FLU regimen (referred to as TBF) has shown promising control of leukemia, and has emerged as a standard regimen in cord blood (CB) transplants (BMT 2012; 47: 1287). The question is whether this holds true also for transplants other than CB grafts.

Aim of the study : to compare Bu-FLU with TBF in patients with AML or RAEB, grafted in remission from related or unrelated donors.

Methods: Eligible for this study were patients allografted between January 2008 and April 2017 with AML or RAEB in hematologic remission . Seventy-eight patients received the BU-FLU regimen (busulfan 3.2 mg/kg/day x4; and fludarabine 40 mg/m^2/day x4), and 127 received TBF( thiotepa 5mg/kgx2, busulfan 3.2 mg/kg/dayx3, fludarabine 50 mg/m^2x3). Graft-versus-host disease (GVHD) prophylaxis was as follows: in HLA identical sibling transplants , cyclosporin (CyA) and Metothrexate (MTX); in unrelated donor transplants CyA+MTX+ antithymocyte globulin (ATG) and for family haploidentical donors (HAPLO) , CyA, mycophenolate mofetil (MMF) and cyclofosphamide 50mg/kg given on day +3 and +5, after transplantation (PT-CY) . Supportive care and infectious disease prophylaxis, or pre-emptive therapy, were provided as per Institutional protocols. Clinical characteristics are shown in Table 1.

Results: With a median follow up of 481 and 551 days (range, 8-2625 and 2-2277 respectively) after transplantation, the 5-year cumulative incidence of TRM was 25% and 9% for BU-FLU and TBF (p = 0.007); the 5-year cumulative incidence of leukemia relapse related deaths (RRD) was 33% and 9% (P = 0.008). TBF showed an advantage over BU-FLU, also after exclusion of HAPLO, both in TRM (p=0.08) and RRD (p=0.04). The 5-year actuarial survival was 41% (26-56%) and 82% (74- 90%) (p=0.000) respectively for the BUFLU and the TBF group. The survival advantage was seen also when looking only at HLA identical siblings and UD, excluding HAPLO grafts (51% vs 82%,p=0.05).

In a multivariate Cox analysis, after correcting for patients age, interval diagnosis transplant, first or second remission , and donor type, the use of TBF reduced the risk of death as compared to BU-FLU (RR 0.3 , range 0.10-0.89, p=0.01) . This was true also when running a Cox model on TRM (RR 0.17 for TBF vs BU-FLU, p=0.02) . TRM was 4% vs 14% in patients receiving TBF vs Bu-FLU aged < 50 years (p=0.09), and 9% vs 32% in patients receiving TBF aged > 50 years (p=0.01). In a Cox analysis on RRD, TBF showed a reduced risk (RR 0.41) but this did not reach statistical significance (p=0.1)

Conclusions: Superior survival of patients receiving TBF , as compared to BU-FLU appears to be a combination of reduced toxicity and reduced relapse. The survival advantage is independent of donor type, and therefore of GvHD prophylaxis.

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